ABSTRACT The eradication of Human Immunodeficiency Virus (HIV-1) from infected individuals is the ultimate goal of antiretroviral therapy. Major advances have been made towards this end with the advent of HAART regimens. Despite the sustained suppression of plasma viremia below detectable limits in infected patients for 2 or more years on HAART regimens, replication competent virus can still be recovered from a variety of subterfuges within the host, most notably long lived quiescent memory CD4+ lymphocytes. These and other unknown viral reservoirs represent the final impediment to the eradication and clearance of HIV infection. Currently, our understanding of HIV reservoirs in HAART recipients is incomplete, as the anatomical locations and cell types for these persisting viral reservoirs in infected hosts have not yet been completely identified. These major gaps in our understanding of HIV persistence cannot be easily ascertained by the study of human patients. We propose to develop a genetically defined rhesus monkey (RM) model of SIV persistence to determine the mechanisms underlying the development, anatomic sequestration, and evolution of viral reservoirs. To investigate these hypotheses, we propose the following Specific Aims: 1. To develop a genetically defined RM model of SIV persistence on HAART, then model the development and evolution of anatomic SIV reservoirs under therapy. 2. To determine the sources of residual viremia by in vivo CD4+ T cell and macrophage depletion followed by treatment interruption. 3.To determine the impact of therapeutic vaccine-augmented immunity on the SIV reservoir and residual virus RNA levels.